Blood cells such as erythrocytes, leukocytes, lymphocytes, and platelets are present as material components in the blood, which is an indispensable medium for the somatic cells constituting the body, and these blood cells each have an inherent function in the continual maintenance of the body. Understanding the phenomenon of the differentiation, maturation, proliferation, and the like of these blood cells in the body has long been the subject of research in the field of hematology, but the differentiation and maturation of various blood cells from one type of multifunctional hematopoietic stem cell in the marrow, the roles played by various endogenous humoral factors during the process of differentiation and maturation, and, other facts have recently been elucidated.
In light of such facts, these endogenous humoral factors hold promise as medicinal products such as drugs for the treatment of diseases associated with decreases in the blood cells of the blood cell systems, and a variety of humoral factors, such as erythropoietin, G-CSF, GM-CSF, M-CSF, and interleukin, have thus far been discovered, some of which have been put to actual use as drugs having action in promoting the differentiation and maturation of blood cells such as those in the erythrocyte, leukocyte, and lymphocyte systems.
Platelets, however, are anucleate cells with a diameter of 2 to 3 .mu.m in the blood, and although they are a type of material component in the blood that plays an important role in hemostatis or thrombogenesis in the body, it has become clear that platelets are formed as a result of the fragmentation of the cytoplasm of megakaryocytes which have matured following the transition from multifunctional hematopoietic cells in the marrow to megakaryoblasts by way of megakaryocyte precursor cells.
There have recently been various reports on the results of research on the megakaryocyte-platelet system. For example, it has been reported that IL-6 has action in promoting the maturation of megakaryocytes, which are precursor cells of platelets (Toshiyuki Ishibashi, et al., Proc. Natl. Acad. Sci. USA., Vol. 86, pp. 5953-5957 (1989), and Toshiyuki Ishibashi, et al., Blood., Vol. 74, pp. 1241-1244 (1989)).
Based on research thus far undertaken, two factors having different types of action are believed to exist in the formation of megakaryocyte colonies from bone marrow cells (N. Williams, et al., J. Cell Physiol., 110, 101 (1982)). Specific examples of such factors which have been reported include megakaryocyte colony stimulating factor (Meg-CSF) which forms megakaryocyte colonies on its own, and megakaryocyte potentiator factor (Meg-POT) which has no activity in forming megakaryocyte colonies in itself but does have activity in increasing megakaryocyte colonies in the presence of Meg-CSF and in promoting their maturation.
Examples that have been reported as having Meg-CSF activity in humans include IL-3 (M. Teramura, et al., Exp. Hematol., 16, 843 (1988)), granulocyte-macrophage colony stimulating factor (M. Teramura, et al., Exp. Hematol., 17, 1011 (1989)), and c-Mpl ligand (F. J. de Sauvage, et al., Nature, 369, 533 (1994), and K. Kaushansky, et al., Nature, 369, 568 (1994)). Examples that have been reported as having Meg-POT activity include IL-6 (M. Teramura and H. Mizoguchi, Int. J. Cell Cloning, 8, 245 (1990)), IL-11 (M. Teramura, et al., Blood, 79, 327 (1992)), and erythropoietin (E. Bruno, et al., Blood, 73, 671 (1989)).
Most of these factors, however, do not have action specific to the megakaryocyte-platelet system. Their activity is known to be expressed as a result of their action on other blood cell systems and on cells other than those of the blood cell systems. As such, even if these were to be administered as medicines in anticipation of their action on the megakaryocyte-platelet system, there is the danger that activity other than the foregoing activity might also be expressed. That is, the aforementioned IL-6, for example, has various other types of action in addition to the aforementioned action, one example of which is that it is known to play a significant role in provoking inflammation as an endogenous acute phase protein, thus suggesting that the use of IL-6 as a medicine might run the risk of serious side-effects.
In light of this, it is important to discover, among factors having action on the megakaryocyte-platelet system, a physiologically active substance that has specific action on said megakaryocyte-platelet system and that is highly active in promoting differentiation and maturation therein, and there is currently a strong need to develop such a physiologically active substance in the relevant fields.